1. Field of the Invention
This invention relates to methods of bone healing and fracture repair.
2. Background Information
Approximately 8-10 million bone fractures are reported annually in the United States with more than 1 million of these requiring hospitalization. The estimated annual costs of treating these fractures exceeds 20 billion dollars. While this is already significant, these numbers are expected to increase due to the aging of the general population. Even though several therapies are indicated for preventing the bone loss associated with aging, there are fewer therapies indicated for treatment once a fracture has occurred. Most of these require local administration which is undesirable due to the complexity of delivery and poor patient compliance. Therefore, it would be desirable to have additional methods of facilitating bone healing and fracture repair.
It has recently been reported that intermittent treatment with parathyroid hormone (PTH) improves fracture healing in ovariectomized rats, indicating that PTH treatment may be potentially useful in treating postmenopausal osteoporotic fractures. xe2x80x9cEffect of Recombinant Human (1-84) Parathyroid Hormone on Fracture Healing in Ovariectomized Rats,xe2x80x9d H. W. Kim et al.; Transactions of the 43rd Annual Meeting of the Orthopaedic Research Society, Vol. 22, Section 1, Abstract 181-31, Feb. 9-13, 1997, and xe2x80x9cIntermittent Treatment of PTH Improves Fracture Healing in OVX Rat,xe2x80x9d H. W. Kim et al.; Journal of Bone and Mineral Research, Vol. 11, Supplement 1, page S152, Abstract P248 (August 1996). Other investigators have reported that implantation of a gene activated matrix expressing bone morphogenetic protein-4 and/or a fragment of PTH (amino acids 1-34) into the segmented defect rat fracture model causes formation of new bone which bridges the gap more rapidly than an untreated control. xe2x80x9cStimulation of New Bone Formation by Direct Transfer of Osteogenic Plasmid Genes,xe2x80x9d Jianming Fang et al.; Proc. Natl. Acad. Sci. (USA), Vol. 93:5753-5758 (June 1996). Various PTH analogs have also been reported to be useful for treatment of osteoporosis (U.S. Pat. Nos. 5,556,940 and 5,559,792). Other methods of fracture healing include the use of is human platelet factor 4 (U.S. Pat. No. 5,622,935), benzothiophenes (U.S. Pat. No. 5,502,074) and 24,25(OH)2 vitamin D3 (U.S. Pat. No. 5,069,905).
PTH related peptide (PTHrP), previously known as the factor responsible for humoral hypercalcemia of malignancy, is a peptide of 138-174 amino acids (depending on alternative splicing) which binds to the PTH/PTHrP receptor. The N-terminal 34 amino acid sequence of PTHrP is of limited sequence homology to that of PTH, but in certain cases shows similar activity to PTH. However, PTHrP is generally less potent and less bone anabolic than PTH and has not been associated with fracture healing. The sequence of hPTHrP (1-34) is as follows:
Several truncated homologs and analogs of PTHrP have been reported. Analogs in which amino acid residues 22-31 of PTHrP(1-34) are replaced by an amphipathic xcex1-helix (U.S. Pat. No. 5,589,452 and WO 97/07815) and related derivatives have been described as useful for treating osteoporosis. xe2x80x9cRS-66271, A C-terminally Substituted Analog of Human Parathyroid Hormone-Related Protein (1-34) Increases Trabecular and Cortical Bone in Ovariectomized, Osteopenic Rats,xe2x80x9d B. H. Vickery et al. J. Bone and Mineral Research, 11(12):1943-1951 (1996) and xe2x80x9cModulation of Osteogenic Cell Ultrastructure by RS-23581, an Analog of Human Parathyroid Hormone (PTH)-Related Peptide-(1-34) and Bovine PTH-(1-34),xe2x80x9d D. Leaffer et al. Endocrinology, 136(8):3624-3631 (1995). Monocyclic and bicyclic analogs of PTHrP (1-34) and PTHrP(7-34) were shown to bind strongly to the PTH receptor and stimulate (or antagonise) PTH-stimulated adenyl cyclase activity in osteoblast-like cells. xe2x80x9cMono- and Bicyclic Analogs of Parathyroid Hormone-Related Protein. 1. Synthesis and Biological Studies,xe2x80x9d Michael Chorev et al. Biochemistry, 36:3293-3299 (1997), and xe2x80x9cCyclic analogs of PTH and PTHrP,xe2x80x9d WO 96/40193.
In one aspect, this invention provides methods of bone healing and fracture repair comprising administering to a patient in need thereof an effective amount of a polypeptide analog of parathyroid hormone related peptide (PTHrP) and salts thereof, wherein amino acid residues 22-31 form an amphipathic xcex1-helix composed of hydrophilic amino acids (Haa) and lipophilic amino acids (Laa) ordered in the sequence:
Haa(Laa Laa Haa Laa)2Laa 
When illustrative embodiments of this amphipathic helix are inserted into the PTHrP sequence, particularly into N-terminal truncates of human PTHrP (residues 1-32 through 1-38), the resulting polypeptides are effective in bone healing and fracture repair. Systemic administration is a preferred mode of delivery.